This application is a revised resubmission of R01 DA022284, initially reviewed by NIDA-L in June 2006. The application proposes a randomized, placebo-controlled trial of bupropion + cognitive behavioral therapy (CBT) to evaluate the efficacy of this combined therapy for attention deficit hyperactivity disorder (ADHD) in adolescents in whom these disorders commonly co-occur. ADHD is one of the most common co-occurring psychiatric disorders (30-50%) in adolescents with substance use disorders (SUD) and has been associated with more severe drug abuse, school failure, long-term psychosocial impairment, and poorer substance treatment outcomes. Research has shown that bupropion is a safe and effective treatment for both ADHD and nicotine dependence in individuals without SUD, and newer research provides empirical support for its unique pharmacotherapeutic properties and potential for treating other addictive disorders (e.g., methamphetamine dependence, pathological gambling). No controlled studies have yet evaluated bupropion's safety and efficacy for ADHD and SUD (including nicotine and cannabis) in adolescents. The lack of research on the safety and efficacy of medications in adolescents with SUD and psychiatric comorbidities contributes to a serious lack of integrated treatment for commonly co-occurring mental health and substance problems in community-based adolescent drug treatment programs. This then contributes to poorer treatment outcomes and prognosis for the large number of comorbid youths with substance abuse and mental health problems that significantly impact public health. The specific aims of the proposed study will address this research gap by conducting a 16-week randomized controlled trial of bupropion vs. placebo to evaluate the safety and efficacy of this low abuse potential medication on ADHD, nicotine dependence, and cannabis use disorders (not excluding other SUD) in 130 adolescents (13-19) receiving concurrent outpatient substance treatment (CBT). The study design and analytic approach will enable assessment of the complex inter-relationship between change in ADHD, depression/dysphoria (and other psychiatric symptoms) and change in nicotine, cannabis and other substance use within and between treatment groups. Thus, the application addresses important research gaps in at least two priority areas of the NIDA/NIH research agenda: 1) research on effective treatments for adolescents with addiction and psychiatric comorbidity, and 2) medications development research for nicotine and cannabis use disorders in adolescents.